rs1395588502

Variant names:

• chr21-36070400-C-A
• rs1395588502
• NM_001757.4:c.285C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001757.4(CBR1):​c.285C>A​(p.Phe95Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CBR1 NM_001757.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.791
• Publications: 0 publications found

Genes affected

CBR1 (HGNC:1548): (carbonyl reductase 1) The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2013]

SETD4 (HGNC:1258): (SET domain containing 4) Enables histone methyltransferase activity (H4-K20 specific). Involved in histone H4-K20 trimethylation. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000289001 (HGNC:):

CBR1-AS1 (HGNC:55777): (CBR1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001757.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBR1	NM_001757.4	MANE Select	c.285C>A	p.Phe95Leu	missense	Exon 1 of 3	NP_001748.1	P16152-1
	CBR1	NM_001286789.2		c.285C>A	p.Phe95Leu	missense	Exon 1 of 3	NP_001273718.1	P16152-2
	CBR1-AS1	NR_040084.1		n.463G>T		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBR1	ENST00000290349.11	TSL:1 MANE Select	c.285C>A	p.Phe95Leu	missense	Exon 1 of 3	ENSP00000290349.6	P16152-1
	CBR1	ENST00000439427.2	TSL:1	c.285C>A	p.Phe95Leu	missense	Exon 1 of 2	ENSP00000395132.2	E9PQ63
	CBR1	ENST00000530908.5	TSL:1	c.285C>A	p.Phe95Leu	missense	Exon 1 of 3	ENSP00000434613.1	P16152-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000426 AC: 1 AN: 234524 AF XY: 0.00000783

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000963

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450250 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720468

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00 AC: 0 AN: 84888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105974

Other (OTH) AF: 0.0000167 AC: 1 AN: 59894

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.025	N
PhyloP100		0.79
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.24
Sift	Benign	0.13	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.88
MutPred		0.47		Loss of catalytic residue at F95 (P = 0.0025)
MVP		0.11
MPC		0.34
ClinPred		0.48	T
GERP RS		2.9
PromoterAI		0.13	Neutral
Varity_R		0.64
gMVP		0.70
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1395588502; hg19: chr21-37442698;